BioSeek: Differentiating p38MAPK Inhibitors - Bridging the Gap from In Vitro to In Vivo

THE CHALLENGE
Our client, a global integrated pharmaceutical company, entered the lead optimization stage with three p38MAPK antagonists. All three compounds were competitive inhibitors for ATP binding and indicated to treat rheumatoid arthritis (RA). At the time the client approached BioSeek, data from biochemical p38MAPK assays and THP1 monocyte cell-line-based assays were generated but failed to show differences among the leads. For example, the compounds had similar IC50 values in biochemical assays of p38MAPK, and appeared to be equipotent at inhibiting TNFα expression in the activated THP-1 human monocytic leukemia cell line. None of the information gathered had enabled the client to prioritize one compound over the others for further development. The challenge was to identify physiologically relevant systems that would reveal what earlier studies may have missed: a more complete assessment of on-target and secondary activities in the context of human biology.

Of particular interest was to elucidate off-target and secondary effects of each p38 MAPK inhibitor, which could impact efficacy and drug safety. This knowledge might then inform the selection of the most promising lead for further pre-clinical and clinical studies. The client wanted to gain as much information as possible to bridge the gap between in vitro and in vivo testing to gain insights about potency as well as target specificity in human systems.